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PLETAL TAB 100MG

Therapeutic indications
Pletal is indicated for the improvement of the maximal and pain-free walking distances in patients with intermittent claudication, who do not have rest pain and who do not have evidence of peripheral tissue necrosis (peripheral arterial disease Fontaine stage II).

Posology and method of administration
The recommended dosage of cilostazol is 100 mg twice a day. Cilostazol should be taken 30 minutes before or two hours after breakfast and the evening meal. Taking cilostazol with food has been shown to increase the maximum plasma concentrations (Cmax) of cilostazol, which may be associated with an increased incidence of adverse effects.

Treatment for 16-24 weeks can result in a significant improvement in walking distance. Some benefit may be observed following treatment for 4-12 weeks.

The physician should consider other treatment options if cilostazol is ineffective after six months.

The elderly

There are no special dosage requirements for the elderly.

Children

Safety and efficacy in children have not been established.

Renal impairment

No dose adjustment is necessary in patients with a creatinine clearance of>25 ml/min. Cilostazol is contraindicated in patients with a creatinine clearance of 25 ml/min.

Hepatic impairment

No dosage adjustment is necessary in patients with mild hepatic disease. There are no data in patients with moderate or severe hepatic impairment. Since cilostazol is extensively metabolised by hepatic enzymes, it is contraindicated in patients with moderate or severe hepatic impairment.

Contraindications
' Known hypersensitivity to cilostazol or to any of the excipients

' Patients with any history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopics, whether or not adequately treated, and in patients with prolongation of the QTc interval

Special warnings and precautions for use
Patients should be warned to report any episode of bleeding or easy bruising whilst on therapy. In case of retinal bleeding administration of cilostazol should be stopped. Refer to Sections 4.3 Contraindications and 4.5 Interactions with other medicinal products and other forms of interaction for further advice on bleeding.

Due to cilostazol's platelet aggregation inhibitory effect it is possible that an increased bleeding risk occurs in combination with surgery (including minor invasive measurements like tooth extraction). If a patient is to undergo elective surgery and anti-platelet effect is not necessary, cilostazol should be stopped 5 days prior to surgery.

There have been rare or very rare reports of haematological abnormalities including thrombocytopenia, leucopenia, agranulocytosis, pancytopenia and aplastic anaemia (see section 4.8). Most patients recovered on discontinuation of cilostazol. However, some cases of pancytopenia and aplastic anaemia had a fatal outcome.

In addition to reporting episodes of bleeding and easy bruising, patients should be warned to promptly report any other signs which might also suggest the early development of blood dyscrasia such as pyrexia and sore throat. A full blood count should be performed if infection is suspected or there is any other clinical evidence of blood dyscrasia. Cilostazol should be discontinued promptly if there is clinical or laboratory evidence of haematological abnormalities.

Caution is advised when cilostazol is co-administered with inhibitors or inducers of CYP3A4 and CYP2C19 or with CYP3A4 substrates. See section 4.5 for further information.

Caution should be exercised when prescribing cilostazol for patients with atrial or ventricular ectopy and patients with atrial fibrillation or flutter.

Caution is needed when co-administering cilostazol with any other agent which has the potential to reduce blood pressure due to the possibility that there may be an additive hypotensive effect with a reflex tachycardia. Refer also to Section 4.8.

Caution should be exercised when co-administering cilostazol with any other agents that inhibit platelet aggregation. Refer to section 4.5 Interactions with other medicinal products and other forms of interaction.

Interaction with other medicinal products and other forms of interaction
Inhibitors of platelet aggregation

Cilostazol is a PDE III inhibitor with anti-platelet activity. In a clinical study in healthy subjects, cilostazol given 150mg b.i.d. for five days did not result in prolongation of bleeding time.

Aspirin

Short term ( 4 days) co-administration of aspirin with cilostazol suggested a 23-25% increase in inhibition of ADP-induced ex vivo platelet aggregation when compared to aspirin alone.

There were no apparent trends toward a greater incidence of haemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.

Clopidogrel and other antiplatelet drugs

Concomitant administration of cilostazol and clopidogrel did not have any effect on platelet count, prothrombin time (PT) or activated partial thromboplastin time (aPTT). All healthy subjects in the study had a prolongation of bleeding time on clopidogrel alone and concomitant administration with cilostazol did not result in a significant additional effect on bleeding time. Caution is advised when co-administering cilostazol with any drug that inhibits platelet aggregation. Consideration should be given to monitoring the bleeding time at intervals. Special attention should be paid to patients who are receiving multiple anti-platelet therapies.

Oral Anticoagulants like warfarin

In a single-dose clinical study, no inhibition of the metabolism of warfarin or an effect on the coagulation parameters (PT, aPTT, bleeding time) was observed. However, caution is advised in patients receiving both cilostazol and any anticoagulant agent, and frequent monitoring is required to reduce the possibility of bleeding.

Cytochrome P-450 (CYP) enzyme inhibitors

Cilostazol is extensively metabolised by CYP enzymes, particularly CYP3A4 and CYP2C19 and to a lesser extent CYP1A2. The dehydro metabolite, which has 4-7 times the potency of cilostazol in inhibiting platelet aggregation, appears to be formed primarily via CYP3A4. The 4`-trans-hydroxy metabolite, with potency one-fifth that of cilostazol, appears to be formed primarily via CYP2C19. Therefore, drugs inhibiting CYP3A4 (e.g., some macrolides, azole antifungals, protease inhibitors) or CYP2C19 (like proton pump inhibitors, PPIs) increase the total pharmacological activity by 32 and 42%, respectively and could have the potential to enhance the undesirable effects of cilostazol. A dose reduction to cilostazol 50 mg b.i.d. could be considered based on the individual clinical and tolerance response.

Administration of 100 mg cilostazol on the seventh day of erythromycin (a moderate inhibitor of CYP3A4) 500 mg t.i.d. resulted in an increase in the AUC of cilostazol by 74%, accompanied by a 24% decrease in AUC of the dehydro metabolite but with notable increases in AUC of the 4`-trans-hydroxy metabolite.

Co-administration of single doses of ketoconazole (a strong inhibitor of CYP3A4) 400 mg and cilostazol 100 mg resulted in a 117% increase in the AUC of cilostazol, accompanied by a 15% decrease in the AUC of the dehydro metabolite and a 87% increase in the AUC of the 4`-trans-hydroxymetabolite, which finally increases the total pharmacological activity by 32% as compared to cilostazol alone.

Administration of 100 mg cilostazol b.i.d. with diltiazem (an inhibitor of CYP3A4) 180 mg once daily resulted in an increase in the AUC of cilostazol by 44%. Co-administration did not affect exposure to the dehydro metabolite but increased by 40% the AUC of the 4`-trans-hydroxy metabolite. In patients in clinical trials, concomitant use with diltiazem was shown to increase the AUC of cilostazol by 53%.

Administration of a single dose of 100 mg cilostazol with 240 ml grapefruit juice (an inhibitor of intestinal CYP3A4) did not have a notable effect on the pharmacokinetics of cilostazol.

Administration of a single dose of 100 mg cilostazol on the seventh day of omeprazole (an inhibitor of CYP2C19) 40 mg once daily increased the AUC of cilostazol by 26%, accompanied by a 69% increase in the AUC of the dehydro metabolite and a decrease of 31% in the AUC of the 4`-trans hydroxy metabolite, which finally increases the total pharmacological activity by 42% as compared to cilostazol alone.

Cytochrome P-450 enzyme substrates

Cilostazol has been shown to increase the AUC of lovastatin (sensitive substrate for CYP3A4) and its β-hydroxy acid by 70%. Caution is advised when cilostazol is co-administered with CYP3A4 substrates with a narrow therapeutic index (e.g., cisapride, halofantrine, pimozide, ergot derivates). Caution is advised in case of co-administration with simvastatin.

Cytochrome P-450 enzyme inducers

The effect of CYP3A4 and CYP2C19 inducers (such as carbamazepin, phenytoin, rifampicin and St. John's wort) on cilostazol pharmacokinetics has not been evaluated. The antiplatelet effect may theoretically be altered and should be carefully monitored when cilostazol is co-administered with CYP3A4 and CYP2C19 inducers.

There are no adequate data in the use of cilostazol in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for humans is unknown. Pletal should not be used during pregnancy.

Lactation

The transfer of cilostazol to breast milk has been reported in animal studies. The excretion of cilostazol in human milk is unknown. Due to the potential harmful effect in the newborn child breast fed by a treated mother, the use of Pletal is not recommended during breast feeding.

Effects on ability to drive and use machines
Cilostazol may cause dizziness and patients should be warned to exercise caution before they drive or operate machinery.

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